It is desired by those with skill in the art to develop efficient and reliable synthetic routes to pure and stable forms of pharmaceutical compounds. As examples, the novel heterocyclic compounds disclosed in WO 0056729 demonstrate protective effects against infection of target cells by human immunodeficiency virus (HIV).
The chemotactic cytokines, or chemokines, are a family of proteins, approximately 8-10 kDa in size that function, at least in part by modulating a complex and overlapping set of biological activities important for the movement of lymphoid cells and extravasation and tissue infiltration of leukocytes in response to inciting agents (see, for example: P. Ponath, Exp. Opin. Invest. Drugs, 7:1-18, 1998). The cellular receptors for these proteins are classified based on the chemokine natural ligand. Receptors of the β-chemokines are designated with the prefix “CCR,” whereas the receptors of the α-chemokine are designated with the prefix “CXCR”.
The natural chemokine ligand for the CXCR4 receptor is stromal cell-derived factor-1 (SDF-1). The inhibition of the binding of SDF-1 to CXCR4 by specific small-molecule inhibitors has been shown in a model, to reduce the severity of the pathogenesis of collagen II-induced arthritis (Matthys et al., J. Immunol. 107: 4686-4692, 2001). This model, which is used as a study model for the pathogenesis of rheumatoid arthritis in humans, shows that SDF-1 plays a central role in the pathogenesis of murine collagen induced arthritis. Similarly, the use of small-molecule CXCR4 inhibitors has been shown in a murine model, to reduce a number of pathological parameters related to asthmatic-type inflammation in an allergin-induced inflammation (Lukacs et al., Am. J. Pathology, 160 (4): 1353-1360, 2002).
Two specific chemokine receptors, CXCR4 and CCR5, have been implicated in the etiology of infection by human immunodeficiency virus (HIV). The T cell-line tropic (T-tropic) viral phenotype of HIV requires, for infection, an association with the CXCR4 receptor, which is expressed in the surface of certain cells of the immune system (Carroll et al., Science, 276: 274-276, 1997). Specifically, an interaction between HIV and the CXCR-4 receptor is required for membrane fusion, a necessary step in the infection of the host immune cell.
The novel heterocyclic compounds disclosed in U.S. Pat. Nos. 5,583,131, 5,698,546 and 5,817,807 selectively bind to the CXCR4 receptor, inhibiting the binding of the natural SDF-1 ligand. Such binding may show anti-inflammatory effects. The binding also competitively prevents the binding of the T-tropic HIV with the receptor, and thus imparts a preventative effect against HIV infection.
The compound AMD3100, which is a specific CXCR4 antagonist, has been shown to reduce HIV viral load and X4 (T-tropic) virus levels in humans (D. Schols et al. Presented at: 9th Conference on Retroviruses and Opportunistic Infections, Feb. 24-28, 2002, Washington State Convention and Trade Center, Seattle, Wash.).
This invention describes the processes for the efficient synthesis and isolation of pure forms of these compounds.